Giant Axonal Neuropathy in a Child With Insulin-Dependent Diabetes Mellitus

Hoffman, William H.; Carroll, James E.; Perry, Guy M. L.; Hartlage, Patricia L.; Kaminer, Sharon J.; Flowers, Nancy C.; Oh, Shin J.; Kelly, David R.

doi:10.1177/088307389501000322

Cited by 11 publications

(5 citation statements)

References 28 publications

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“…The presence of bulbous nerve endings and other features suggests that plastic changes are taking place in the sympathetic innervation of the CC. In human type I diabetes 30 and in STZ-diabetic rats, there are reports of the presence of giant axons, and of the presence of aggregates of intra-axonal subcellular organelles. [31][32][33] There are also observations of some regenerative activity in diabetic nerves.…”

Section: Discussionmentioning

confidence: 99%

Long-term changes in sympathetic innervation in the corpus cavernosum of the STZ-diabetic rat

et al. 2007

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The noradrenaline (NA) concentration in the rat corpus cavernosum (CC) increased to approximately 350% of control values after about 8 weeks of hyperglycaemia induced by the intraperitoneal injection of streptozotocin (STZ) at 10 weeks of age. These changes were maintained for at least a further 32 weeks of hyperglycaemia and occurred without any significant change in the weight in the tissue. Smaller but significant increases in NA concentration occurred in the glans penis (GP) reaching 150-175% of the control levels during the period of prolonged hyperglycaemia. In contrast, there was no significant change in the NA concentration in the penile urethra. Measurements have also been made that relate to changes in the synthesis and reuptake of NA in the CC during the period during which high NA concentration is maintained. Immunohistochemical studies for the synthetic enzyme tyrosine hydroxylase in the CC indicate that the intensity of staining in the tissue had increased after 10, 20 and 32 weeks of hyperglycaemia, relative to the tissues from control animals. Dilated nerve fibres and engorged endings were present in the CC of the diabetic animals at these times. Reuptake of tritiated NA by the terminal axonal membranes in the CC was raised to 181% of control values after 12 weeks of hyperglycaemia (Po0.05), but later declined to values that are not significantly different from the control levels (after 26 and 64 weeks of hyperglycaemia). There are few studies of the effects of prolonged diabetes on functional aspects of sympathetic postganglionic neurones in the CC, and this paper suggests that the changes described represent remodelling of noradrenergic axonal terminals starting about after 8-10 weeks of hyperglycaemia; this delay in onset of the neuropathic changes is also a feature of type I diabetes in humans.

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Section: Discussionmentioning

confidence: 99%

Long-term changes in sympathetic innervation in the corpus cavernosum of the STZ-diabetic rat

et al. 2007

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“…Thus, they proposed that defects in a second locus, GAN2, underlie the disorder in this Algerian family. It was also suggested that a link may exist between GAN and insulin-dependent diabetes mellitus [22]. As an important step in understanding the pathogenesis of GAN, Koenig and colleagues successfully cloned the GAN gene and identified mutations of the locus [23].…”

Section: Geneticsmentioning

confidence: 98%

Giant axonal neuropathy

Yang

Allen

Ding

et al. 2007

Cell. Mol. Life Sci.

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Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder affecting both the central and peripheral nervous systems. Cytopathologically, the disorder is characterized by giant axons with derangements of cytoskeletal components. Geneticists refined the chromosomal interval containing the locus, culminating in the cloning of the defective gene, GAN. To date, many distinct mutations scattered throughout the coding region of the locus have been reported by researchers from different groups around the world. GAN encodes the protein, gigaxonin. Recently, a genetic mouse model of the disease was generated by targeted disruption of the locus. Over the years, the molecular mechanisms underlying GAN have attracted much interest. Studies have revealed that gigaxonin appears to play an important role in cytoskeletal functions and dynamics by directing ubiquitin-mediated degradations of cytoskeletal proteins. Aberrant accumulations of cytoskeletal-associated proteins caused by a defect in the ubiquitin-proteasome system (UPS) have been shown to be responsible for neurodegeneration occurring in GAN-null neurons, providing strong support for the notion that UPS plays crucial roles in cytoskeletal functions and dynamics. However, many key questions about the disease remain unanswered.

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“…Gastrointestinal symptoms, including constipation, reflux and regurgitation, and lactose intolerance, have been reported. There are also reports of diabetes and renal tubular acidosis associated with GAN. Patients have a characteristic physical appearance, with high foreheads, pale complexions, and long eyelashes.…”

Section: Clinical Presentation and Symptomsmentioning

confidence: 99%

Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis

et al. 2014

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Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the "giant" axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot-Marie-Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as "giant axonal neurodegeneration."

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Giant Axonal Neuropathy in a Child With Insulin-Dependent Diabetes Mellitus

Cited by 11 publications

References 28 publications

Long-term changes in sympathetic innervation in the corpus cavernosum of the STZ-diabetic rat

Long-term changes in sympathetic innervation in the corpus cavernosum of the STZ-diabetic rat

Giant axonal neuropathy

Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis

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